CHOLINERGIC ANTAGONISTS“ANTICHOLINERGIC DRUGS”

(PARASYMPATHOLYTICS)

PHARMACOLOGY I/ ANS, LECTURE 4 DR. HIWA K. SAAED, HD, MSC. PHD

PHARMACOLOGY & TOXICOLOGY

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Drugs that block cholinergic receptors (M and/or N).

The actions of sympathetic stimulation are left unopposed.

Cholinergic antagonists

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They are classified to two subclasses:1. Muscarinic (M1-M5) receptor

antagonists: the most useful clinically.2. Nicotinic receptor antagonists: further subdivided to:

NMJ Blocking agents: inhibit the efferent impulses to skeletal muscle via the (NM) receptor

Ganglionic Blocking agents: inhibit the nicotinic neuronal receptor (NN) of both parasympathetic and sympathetic ganglia

Cholinergic antagonists

Sites of action of cholinergic antagonists

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Muscarinic antagonists:

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Atropine (prototype): comes from the plant Atropa belladonna and is known as a belladonna alkaloid. Belladonna in Latin means pretty lady. Inhibit all M functions.

Scopolamine (hyoscine): Rx of motion sickness ; natural occurring alkaloid

Propantheline, Dicyclomine: Rx of peptic disease, hypermotility

Clidinium (Librax), isopropamide (stelabid), Mebeverine (Duspataline)

Homatropine:Cyclopentolate, Tropicamide: mydriasis and cycloplegia

Pirenzepine & telenzipine: Selective M1 blocker. Rx of Gastric ulcer

Oxybutinin: somewhat selective for M3 receptors

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Trospium: nonselective comparable in efficacy and SE with oxybutinin

Darifenacin and Solifenacin: selective M3 blocker

Tolterodine: selective M3 blocker Rx of urinary incontinence

Flavoxate: also indicated for overactive bladder

Benztropine: Rx of ParkinsonismIpratropium, Tiotropium: Rx of Asthma

*Imipramine a TCA with strong antimuscarinic actions, has long been used to reduce incontinence in elderly

Muscarinic antagonists:

Atropine (hyoscyamine) Mechanism of action:

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It causes reversible, nonselective blockade of muscarinic receptors.

Therefore, High concentration of Ach or an equivalent muscarinic agonists can be used to counteract the effects of atropine

Pharmacologic actions of atropine

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CNS: at toxic doses can cause- restlessness, - hallucinations, - and delusions.CVS: At low doses, atropine reduces heart

rate through central stimulation of the vagus nucleus.

At high doses, atropine blocks muscarinic receptors of the heart and thus induces tachycardia

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GIT: reduces salivary gland secretion and GI motility.

Pulmonary system: reduces bronchial secretions and stimulates bronchodilation.

Urinary system: blocks muscarinic receptors in the bladder wall, which results in bladder wall relaxation.

Eye: causes paralysis of the sphincter muscle of the iris and ciliary muscle of the lens, resulting in mydriasis and cycloplegia

Sweat glands: Suppresses sweating, especially in children.

Pharmacologic actions of atropine

Atropine effects in order of increasing dose

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Decreased secretions (Salivary, bronchiolar, sweat)

Mydriasis and cycloplegiaHyperthermia (vasodilation)TachycardiaSedationUrinary retention and

constipationBehavioral excitation and

hallucinations

Therapeutic uses of atropine

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BradycardiaMydriasis and cycloplegia- beneficial when a

thorough fundus examination or an accurate refraction is required.

NB: atropine contraindicated in a patients who has narrow-angle glaucoma, because this may result in acute crisis due to closure of the canal of Schlemm

GIT and bladder spasms: organophosphate poisoning.

Pharmacokinetics

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Atropine as a tertiary amine, it is well absorbed from the GIT and conjunctival membrane.

It is excreted through both hepatic metabolism and renal function.

Atropine’s duration of action is ~ 4 hrs, except when it is placed in the eye, where it usually lasts about 14 days

Adverse effects

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Dry mouth (dry as bone) Inhibition of sweating especially in

young children (hot as a hare)Tachycardia and coetaneous

vasodilation (red as beet)Blurring of vision (blind as a bat)Hallucinations and delirium (mad as

a hatter)

Urine retention

Scopolamine

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Like atropine, this drug is a belladonna alkaloid.

But it has a longer duration of action and more potent CNS effect

Nonselective competitive blockade of muscarinic receptors

Therapeutic uses: Prevention of motion sickness

Adverse effects: similar to those of atropine

Others:Homatropine, cyclopentolate & Tropicamide: In ophthalmology, they are given topically for mydriasis and cycloplegia.Pirenzepine: a selective M1 muscarinic inhibitor, used for treating gastric ulcers

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2. Neuromuscular blocking agents

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NM blockers

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I. Nondepolarizing blocking agents (antagonists)

1. Tubocurarine (prototype)2. Pancuronium: longer duration of action3. Atracurium4. VecuroniumII. Depolarizing blocking agents (agonists):5. Succinylcholine3-6 minutes if given as a single dose.Metabolized by plasma cholinesterase

Mechanism of action: At low dose: these drugs competitively

block cholinergic transmission at the nicotinic receptors by preventing the binding of Ach to its receptor.

Their action can be reversed with edrophonium or neostigmine ????

At high dose: block the ion channels of the end plate. This action can not be reversed by CE inhibitors.

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I. Nondepolarizing NM blockers

I. Nondepolarizing NM blockers

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All NM junction blockers must be given I.V because oral absorption is poor.

Therapeutic use: They are used as adjuvant drugs for anesthesia-

they promote muscle relaxation; the muscle of the eye and face are affected first, whereas the respiratory muscles are affected last.

Sequence of Paralysis

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Fingers, orbit (small muscles)

limbs Trunk neck

IntercostalsDiaphragm

Recovery in Reverse

II. Depolarizing NM junction blockers

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Succinylcholine: Mech. of action: Phase I- opens the Na

channels-membrane depolarization-transient fasciculations. Flaccid paralysis will follow in a few minutes

Phase II: the membrane partially repolarize. However, these receptors are now desensitized to Ach, Thus preventing the formation of further action potentials. In other words, is now acting in a manner similar to tubocurarine.

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1. As an adjuvant to GA to facilitate rapid intubation.

2. Orthopedic procedures for alignment of fractures.

3. In electroshock treatment of psychiatric disorders.

Therapeutic Use

Drug Interaction

Cholinesterase inhibitors: can overcome the action of nondepolarizing neuromuscular blockers

Halogenated hydrocarbon anesthetics: Drugs such as halothane sensitize the neuromusclular junction to the effects of neuromuscular blockers.

Aminoglycoside antibiotics: inhibit Ach release from cholinergic nerves by competing with calcium ions. (Synergistic)

Calcium-channel blockers: These agents may increase the neuromuscular block of tubocurarine and other competitive blockers as well as depolarizing blockers.

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Adverse effects of NM blockers:

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1. Bronchoconstriction caused by histamine release

2. Decreased tone and motility in GI tract3. Depolarizing agents can cause increased K+

efflux in patients with burns, trauma, or denervation and lead to hyperkalemia

4. Hypotension5. Arrhythmias6. Apnea due to respiratory paralysis (check for

psudocholinesterase genetic polymorphism)7. Malignant hyperthermia

(succinylcholine+halothane especially); Rx by dantroline. It blocks the release of Ca+2 from

the sarcoplasmic reticulum which subsequently reduces skeletal muscle contraction.

Q. Do NM junction blocking agents block autonomic ganglia as well???

Classification of BlockersAgent Pharmacological

PropertiesOnset time

(min)Duration

(min)Elimination

Succinylcholine Ultra-short acting;Depolarizing 1-1.5 6-8

Plasma cholinesterase

D-tubocurarine Long duration;Competitive 4-6 80-120

Renal and liver

Atracurium Intermediate duration;Competitive

2-4 30-40Plasma cholinesterase

Mivacurium Short duration;Competitive 2-4 12-18

Plasma cholinesterase

Pancuronium Long duration;Competitive 4-6 4-6

Renal and liver

Rocuronium Intermediate duration;competitive

1-2 1-2Renal and liver

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3. Ganglionic blockers

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Nicotine, Hexamethonium, Mecamylamine, Trimethaphan

Ganglionic blockers compete with Ach to bind with nicotine receptors of both Parasympathetic and Sympathetic ganglia

Ganglionic blockers divided into two groups:

1. Drugs such as nicotine, which initially stimulate the ganglia and then block them because of a persistent depolarization

2. Drugs such as hexamethonium, mecamylamine, and trimethaphan, which block ganglia without any prior stimulation.

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The physiologic effects of ganglionic blockers can be predicted depending on which division of the ANS exercises dominant control of the organ in question:

Heart: tachycardia results because the parasympathetic system is normally dominant on the heart.

Arterioles and veins: vasodilation, increased peripheral blood (sympathetic normally dominant)

3. Ganglionic blockers

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Eye: cycloplegia, mydriasis (parasympathetic normally dominant)

GIT: reduced motility; diminished gastric and pancreatic secretions (parasympathetic normally dominant)

Urinary system: urinary retention (parasympathetic normally dominant)

Sweat glands: reduced sweating (sympathetic normally dominant)

3. Ganglionic blockers

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Therapeutic useBecause they lack the selectivity, the ganglionic

blockers very rarely used clinically. In the past, these drugs were used in

hypertensive emergencies.

3. Ganglionic blockers